Polycythemia vera (PV) is a clonal disorder of unknown etiology arising in a multipotent hematopoietic[unreadable] progenitor cell that is characterized by overproduction of phenotypically normal red cells, white cells and[unreadable] platelets in the absence of a definable cause. Impaired expression of the thrombopoietin receptor, Mpl.[unreadable] occurs in PV and to a lesser extent, idiopathic myelofibrosis (IM) and essential thrombocytosis (ET), while in[unreadable] African Americans, an Mpl point mutation (K39N) was associated with thrombocytosis. Recently, a JAK2[unreadable] point mutation (V617F) was identified in the majority of PV patients and also in some IM and ET patients.[unreadable] The extent to which each of these molecular abnormalities contributes to the PV phenotype and their[unreadable] relationship to each other is unknown but we hypothesize that both contribute and are integrally related.[unreadable] Using gene expression profiling and unsupervised hierarchical clustering in PV peripheral blood CD34+ cells,[unreadable] we have also been able to segregate PV patients into two groups: those with an aggressive disease and[unreadable] those with a more indolent one. Whether these gene expression profiles reflect the functional behavior of the[unreadable] CD34+ cells and how they relate to the JAK2 V617F mutation is unknown. To address these questions, we[unreadable] plan to develop complementary murine models to study the in vitro and in vivo behavior of murine[unreadable] hematopoietic progenitor cells expressing PV variant Mpl or JAK2 V617F alone or together using the Mpl[unreadable] knockout mouse to dissect Mpl and JAK2 V617F interactions. To control for overexpression of either Mpl or[unreadable] JAK2 V617F, we also plan to examine their behavior using conditional expression in murine ES cells from[unreadable] the Mpl knockout mouse. To examine the functional significance of the gene expression profiles, we plan to[unreadable] study the engraftment kinetics of PV CD34+ cells, their lineage-specific commitment and the extent of[unreadable] extramedullary hematopoiesis after transplantation into NOD-SCID mice. Using flow cytometry and[unreadable] xenotransplantation, we also plan to define by immunophenotyping, the class of CD34+ cell involved in PV.[unreadable] PV is not a new disease but after 11 decades of investigation, its etiology remains unknown and[unreadable] there is no specific therapy for it. We propose to develop complementary animal models for PV that will lead[unreadable] to an understanding of the pathogenesis of PV, that will identify PV patients most at risk from disease[unreadable] complications, and provide a means for testing potential treatments for the disorder.